The neuropathology of multiple system atrophy and its therapeutic implications

Valera, Elvira; Masliah, Eliezer

doi:10.1016/j.autneu.2017.11.002

Cited by 38 publications

(28 citation statements)

References 100 publications

(119 reference statements)

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“…Contrary to our rat model of PD, neuronal-targeted TFEB in PLP mice did not afford dopaminergic neuroprotection, reduction of synucleinopathy, or a decrease in inflammatory responses. This lack of efficacy of neuronal expression of TFEB in a MSA model could be due to the fact that, similar to the disease (45), neurons are less affected by the synucleinopathy compared with oligodendrocytes. Surprisingly, neuronal expression of TFEB in both WT and PLP mice showed potent neurotrophic effects, possibly linked to modulation of growth machinery, such as demonstrated in oncology (46), which should be further elucidated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies

Arotcarena¹,

Bourdenx²,

Dutheil³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies

Arotcarena¹,

Bourdenx²,

Dutheil³

et al. 2019

JCI Insight

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“…The pathological hallmark of the disease is a-synuclein positive cytoplasmic inclusions in oligodendroglia (glial cytoplasmic inclusions (GCIs)), however neuronal cytoplasmic and neuronal/glial nuclear inclusions (NCIs, NNIs, GNIs) are also common, while Lewy bodies are identified in only 10% of patients [4,5]. In comparison to Parkinson's disease, the most common a-synucleinopathy, MSA has a more rapid progression and death generally occurs 9 years after the diagnosis [3,[6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Signs of early cellular dysfunction in multiple system atrophy

Herrera‐Vaquero

Heras‐Garvin

Krismer

et al. 2020

Neuropathology Appl Neurobio

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Signs of early cellular dysfunction in multiple system atrophy Aims: Multiple system atrophy (MSA) is a fatal neurodegenerative disease that belongs to the family of asynucleinopathies. At post mortem examination, intracellular inclusions of misfolded a-synuclein are found in neurons and oligodendrocytes and are considered to play a significant role in the pathogenesis. However, the early steps of the disease process are unknown and difficult to study in tissue derived from end-stage disease. Methods: Induced pluripotent stem cells (iPSCs) were generated from patients' and control skin fibroblasts and differentiated into NCAM-positive neural progenitor cells (NPCs). The mitochondrial morphology and function were assessed by immunocytochemistry and high resolution respirometry. The ability to cope with exogenous oxidative stress was tested by exposure to different doses of luperox. The expression of a-synuclein was studied by immunocytochemistry. Results: We identified increased tubulation of mitochondria with preserved respiration profile in MSA-derived NPCs. Exposure of these cells to exogenous oxidative stress even at low doses, triggered an excessive generation of reactive oxygen species (ROS) and cleavage of caspase-3. MSA-derived NPCs did not present changed levels of SNCA gene expression nor intracellular aggregates of a-synuclein. However, we identified disease-related translocation of a-synuclein to the nucleus. Conclusions: Our results show early cellular dysfunction in MSA-derived NPCs. We identified changes in the redox homeostasis which are functionally compensated at baseline but cause increased susceptibility to exogenous oxidative stress. In addition, nuclear translocation of asynuclein in MSA-derived NPCs supports an early cellular stress response which may precede the neurodegenerative process in this disorder.

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“…Moreover, MSA is frequently misdiagnosed, differentiation from other parkinsonian syndromes is difficult and definite diagnosis can only be made post-mortem, which makes the design of clinical trials and stratification of patient cohorts even more challenging [1,203]. In addition, despite transgenic animal models have contributed to identify important aspects of the disease, they artificially overexpress α-syn in oligodendrocytes, thus concealing the mechanism which triggers MSA and the accumulation of α-syn [83,204,205]. Novel strategies targeting α-syn aggregation, such as α-syn immunotherapy and small molecules, hold, however, promising therapeutic potential that still have to be evaluated in human trials [123][124][125]145,148].…”

Section: Discussionmentioning

confidence: 99%

MSA: From basic mechanisms to experimental therapeutics

Heras‐Garvin

Stefanova

2020

Parkinsonism & Related Disorders

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Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by rapidly progressive autonomic and motor dysfunction. Pathologically, MSA is mainly characterized by the abnormal accumulation of misfolded α-synuclein in the cytoplasm of oligodendrocytes, which plays a major role in the pathogenesis of the disease. Striatonigral degeneration and olivopontecerebellar atrophy underlie the motor syndrome, while degeneration of autonomic centers defines the autonomic failure in MSA. At present, there is no treatment that can halt or reverse its progression. However, over the last decade several studies in preclinical models and patients have helped to better understand the pathophysiological events underlying MSA. The etiology of this fatal disorder remains unclear and may be multifactorial, caused by a combination of factors which may serve as targets for novel therapeutic approaches. In this review, we summarize the current knowledge about the etiopathogenesis and neuropathology of MSA, its different preclinical models, and the main disease modifying therapies that have been used so far or that are planned for future clinical trials.

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The neuropathology of multiple system atrophy and its therapeutic implications

Cited by 38 publications

References 100 publications

Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies

Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies

Signs of early cellular dysfunction in multiple system atrophy

MSA: From basic mechanisms to experimental therapeutics

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